Destabilized 3’UTR ARE therapeutically degrades ERBB2 in drug-resistant ERBB2+ cancer models

Breast, lung, and colorectal cancer resistance to molecular targeted therapy is a major challenge and unfavorably impacts clinical outcomes, leading to hundreds of thousands of deaths yearly. In ERBB2+ cancers regardless of the tissue of origin, ERBB2 is the driver oncogene of resistance. We discovered that the ERBB2+ cancers are enriched with poly U sequences on their 3’UTR AU rich elements which are mRNA stabilizing sequences. We developed a novel technology, in which we engineered these ERBB2 mRNA stabilizing sequences to unstable forms and specifically controlled and degraded ERBB2 transcript and protein across multiple cancer types both in the wildtype and drug resistance settings in vitro and in vivo, offering a unique novel modality to control ERBB2 and other pervasive oncogenic signals where other therapies fail.One-Sentence SummaryEngineered destabilized 3’UTR ARE of ERBB2 degrades ERBB2 in many cancer types and controlled resistance.Graphical abstractA. Depiction represents multiple ERBB2 expressing cancer cells with stable 3’UTR ARE and the signaling cascade known to cause chemo resistance. B. Depiction of the engineered destabilized 3’UTR ARE of ERBB2 and the destabilization and degradation of the ERBB2 transcript, protein and kinases involved in mediation of drug resistance